Intranasal delivery systems for traumatic brain injury: Advancements and perspectives

Abstract

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, commonly leading to long-term impairments in cognition, sensorimotor function, and personality. While neuroprotective drugs have demonstrated some efficacy in vitro cultures and in vivo animal models, their clinical applications remain debated. Intranasal delivery to the brain parenchyma, bypassing the blood-brain barrier for more direct access to target sites, offers a favorable and safe approach. This review illuminates current advancements in intranasal delivery systems for TBI treatment. We begin with an overview of TBI and its current clinical treatment options. We then outline recent developments in intranasal delivery systems of molecules and cells, emphasizing their efficacy in animal models. Finally, we discuss future clinical perspectives on emerging trends, offering insights into leveraging intranasal delivery for effective TBI therapeutics.

Keywords: intranasal delivery; nanoparticles; regeneration; stem cells; traumatic brain injury.

Figure 1.

Overview of the pathophysiology, clinical outcomes, and therapeutic strategies in traumatic brain injury (TBI).

Figure 2.

Rodent TBI models and their strengths and limitations.

Figure 3.

Overview of therapeutic strategies for TBI. TBI induces neuronal loss, inflammation, vascular dysfunction, and impaired regeneration. Four major approaches—neuroprotective, anti-inflammatory, neurovascular, and neuroregenerative—target these pathological processes using distinct mechanisms and agents.

Figure 4.

Mechanism of intranasal delivery. Schematic illustration of nose-to-brain transport following intranasal administration of biomolecules or nanoparticles. Upon delivery into the nasal cavity as a spray or drop, therapeutic agents interact with the olfactory mucosa and reach the brain through paracellular, transcellular, and intracellular (axonal) pathways. The paracellular pathway enables passive diffusion of small molecules or nanoparticles through tight junctions between epithelial cells. The transcellular pathway involves endocytic uptake and vesicular transport across epithelial cells, allowing receptor-mediated or adsorptive delivery of macromolecules. In the intracellular pathway, substances are internalized by olfactory sensory neurons and transported via axonal projections into the olfactory bulb and brainstem. These pathways enable direct access to the central nervous system while bypassing the blood-brain barrier, supporting efficient delivery of therapeutics to target brain regions.

Figure 5.

Mechanisms of therapeutic molecules and candidates in TBI. Schematic overview of representative molecular and cellular mechanisms underlying therapeutic strategies for TBI. (a) IGF-1 exerts neuroprotective effects by engaging IGF1R and activating multiple signaling pathways. The RAS–ERK–Akt axis suppresses neuronal apoptosis, while the PI3K–Akt–HO-1 pathway attenuates oxidative stress and inflammation. Concurrently, PI3K–Akt–GLUT signaling enhances glucose uptake and metabolic homeostasis. IGF1R also modulates ion channel activity and neurotransmission through ionic current regulation. (b) BDNF binds to TrkB and initiates downstream cascades that support neuronal growth and plasticity. The PI3K–Akt–mTOR pathway promotes dendritic development and cell survival, whereas the Ras–MEK–ERK and PLC–CaMKII pathways converge on CREB to induce transcriptional programs involved in synaptic remodeling, differentiation, neurotransmitter regulation, and myelination. (c) Exosomes and extracellular vesicles (EVs) deliver bioactive cargos such as miRNAs, lncRNAs, growth factors, and cytokines to injured neural tissue. These components promote neuroregeneration, suppress neuroinflammation (e.g. via IL-4, IL-10), reduce apoptosis through autophagy regulators (LC3B, Beclin-1), and enhance angiogenesis via VEGF-mediated signaling. (d) Stem cells modulate the post-injury brain microenvironment primarily through paracrine mechanisms. They release EVs, trophic factors, and cytokines that collectively support vascular, neuronal, and immune recovery. EV-associated IGF-1, VEGF, ANG-1, and HGF promote angiogenesis; neurotrophic factors (BDNF, NGF, GDNF) facilitate axon growth and myelination; and immunomodulatory cytokines (IL-4, IL-10, IL-13) contribute to neuroprotection, neurite outgrowth, and neurogenesis.

Figure 6.

Overview of biomaterial-based intranasal delivery systems for brain-targeted therapy. Schematic summary of nose-to-brain delivery using biomaterial-based systems, outlining overall advantages and challenges of the approach, along with comparative features of representative nanocarrier platforms.

Figure 7.

Intranasal delivery of biomaterial-based therapeutics for targeted brain treatment after TBI. (a) Intranasally administered IL-4–loaded liposomes reach the injured brain via the olfactory pathway. The released IL-4 activates PPARγ signaling in damaged white matter, promoting oligodendrocyte differentiation and myelin regeneration, thereby improving sensorimotor function. (b) Intranasal delivery of cerebrolysin-loaded PLGA nanoparticles facilitates brain targeting through mucoadhesion and epithelial penetration, followed by transport via the olfactory and trigeminal pathways. Sustained cerebrolysin release within injured regions stabilizes the BBB, reduces neuroinflammation, enhances cognitive function, and protects neural tissue. (c) PEGylated gold nanoparticles (AuNPs) administered intranasally traverse the nasal epithelium via paracellular transport and distribute to multiple brain regions, including the olfactory bulb, hippocampus, brainstem, entorhinal cortex, and periaqueductal gray. In injured tissues, AuNPs downregulate NF-κB–mediated cytokine production and upregulate antioxidant enzymes, attenuating neuronal apoptosis and supporting neuroimmune stabilization, neuroprotection, and behavioral recovery. (d) A thermoresponsive hydrogel encapsulating neuroprotective agents is administered intranasally in liquid form. Upon contact with the nasal mucosa, it undergoes in situ gelation on the olfactory epithelium, forming a mucoadhesive layer that enables sustained drug release. The agents reach the brain via the olfactory nerve pathway, modulating neuroinflammatory responses, promoting neuronal resilience, enhancing cognitive performance, and stabilizing neurovascular function.